Steroidyl-estratrienes

ABSTRACT

BIOLOGICALLY ACTIVE DISTEROIDYL ETHERS CONSISTING OF TWO STERIOD NUCLEI JOINED TOGETHER BY AN OXYGEN BRIDGE ARE PREPARED BY REACTING A 17-HYDROXY ESTRATRIENE WITH AN ENOL ETHER OR AN ACETAL OF A 3-KETOSTERIOD OF THE ANDROSTANCE, GONANE,CHOLESTANE OR PREGNANE SERIES AND THEIR 19-NOR DERIVATIVES. THE REACTION IS CARRIED OUT UNDER ANHYDROUS CONDITIONS AND IN THE PRESENCE OF AN ACID CATALYST, AT A TEMPERATURE HIGHER THAN 70*C.

United States Patent Olfice 3,828,081 STEROIDYL-ESTRATRIENES Alberto Ercoli, Milan, Rinaldo Gardi, Carate Brianza, and Romano Vitali, Casatenovo, Italy, assignors to Warner-Lambert Company, Morris Plains, NJ.

N Drawing. Continuation-impart of abandoned application Ser. No. 129,634, Mar. 30, 1971. This application Jan. 31, 1973, Ser. No. 328,208

Int. Cl. C07c 169/60 U.S. Cl. 260397.2 21 Claims ABSTRACT OF THE DISCLOSURE Biologically active disteroidyl ethers consisting of two steroid nuclei joined together by an oxygen bridge are prepared by reacting a 17-hydroxy estratriene with an enol ether or an acetal of a 3-ketosteroid of the androstane, gonane, cholestane or pregnane series and their 19-nor derivatives. The reaction is carried out under anhydrous conditions and in the presence of an acid catalyst, at a temperature higher than 70 C.

CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of our pending U.S. patent application Ser. No. 129,634, filed Mar. 30, 1971 now abandoned.

SUMMARY OF THE INVENTION It is an object of the present invention to provide new steroid molecules consisting of two hormonal entities different each other in nature and in constitution, which are joined together by an oxygen bridge involving the carbon atoms in the 3- and 17-positions of the reacting steroids.

The new disteroidyl ethers of this invention are derivatives of 17-hydroxy-estratrienes with 3-ketosteroids of the androstane, gonane, cholestane or pregnane series and the 19-nor-derivatives thereof. These compounds can be represented by the following structural formulae I and II:

wherein the wavy lines indicate that the oxygen atom linked in 17-position of the estratriene nucleus and the substituent in position 16' of the second steroid nucleus may assume u or ,3 configuration; the positions of the 3-ket0steroid moiety being marked with the symbol to distinguish them from the corresponding positions of the estratriene moiety;

R represents hydrogen, an acyl radical derived from a hydrocarbon mono-carboxylic or di-carboxylic acid containing up to 12 carbon atoms, a radical of a polybasic inorganic acid; or a hydrocarbon radical selected from the group consisting of aliphatic, cycloaliphatic and aromatic radicals containing up to 9 carbon atoms;

R represents hydrogen or methyl;

R and R represent each hydrogen, hydroxy or an acyloxy group containing up to 4 carbon atoms;

R represents an OAcyl group-in which the Acyl radical is that of a hydrocarbon monocarboxylic or dicarboxylic acid containing up to 12 carbon atoms or is derived from a polybasic inorganic acidwhen R is hydrogen or hydroxy;

R represents an acyloxy group containing up to 7 carbon atoms, inclusive, when R is hydrogen or hydroxy;

R represents hydrogen, halogen, methyl, methylene or an alkanoyloxy radical containing up to 4 carbon atoms;

R and R may form together a cyclopentylidenedioxy radical, or R and R may form together an isopropylidenedioxy radical or a 1"-methylbenzylidenedioxy radical;

Y represents hydrogen, fluoro or chloro;

X represents hydrogen, B-hydroxy, ketonic oxygen, or chloro when also Y represents chloro; the carbon atom at the 17-position of formula I having one of the following structures:

The compounds of the present invention, as defined by the Formulae I and H above, may contain in addition a Patented Aug. 6, 1974.

methyl radical or a halogen atom, particularly fluorine or chlorine, in one or more of the positions 1', 2', 6' and 7'. Further, the 7'positi0n can also be substituted by a thio-acyl group, and a methylene bridge can be also attached to the carbon atoms at the position 1'2 of the compounds of Formula II.

Optional substituents, such as hydroxy, methoxy or halogens may be also contained in position 2 or 6 of the estratriene moiety.

The invention sought to be patented also include certain 17'-spiro lactones of 7'-acy1-thio substituted compounds of Formula I, among which are particularly interesting those compounds wherein the 3-ketosteroid moiety consists of the 17-spiro lactone of 3-keto-7a-acetylthio-androst-4-ene and of its 19-nor-analogue.

The invention further describes certain disteroidyl compounds in which the 3-ketosteroid moiety is formed by aldosterone, isoaldosterone and their 21-ester derivatives.

The acyloxy and acyl radicals which are present in the disteroidyl compounds of this invention preferably derive from organic carboxylic acids containing up to 12 carbon atoms. Particularly, these acids may be monocarboxylic or dicarboxylic acids, saturated or unsaturated, including the aromatic acids, and may contain a straight or branched aliphatic chain, or may be formed by a cycloaliphatic, arylaliphatic or aromatic group. They may also be substituted by alkoxy or amino groups, halogen atoms and the like. Typical esters are the acetate, propionate, butyrate, valerate, enanthatc, caproate and their isomers, the trimethylacetate, aminoacetate, hemisuccinate, phenoxyacetate, phenylpropionate, phenylbutyrate, cyclopentyiacetate, cyclopentylpropionate, cyclohexylacetate, fl-chloropropionate, undecanoate, benzoate, p-chloroor fluoro-benzoate, and the like, the hemioxalate, hemimalonate, hemisuccinate, hemiglutarate, hemiphthalate, salts hexahydro-hemiphthalate and their It may be straight or branched, saturated or unsaturated, and optionally substituted by functional groups. Representative of such radicals are the methyl, ethyl, vinyl, propyl, butyl, amyl, hexyl, heptyl, octyl, nonyl and their isomers, ethoxyethyl, eyclopropyl, cyclopropylmethyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cyclooctenyl, l-methoxycyclopentyl, 1 ethoxycyclopentyl, 1 methoxycyclohexyl, 1- ethoxycyclohexyl, tetrahydropyranyl, benzyl, p-chlorobenzyl and the like.

According to the present invention, the new steroidylestratriencs are prepared by reacting, under proper conditions, a 17-hydroxy estratriene with an activated derivative of a 3-ketosteroid of the androstane, pregnane or cholestane series as well as l8-homo and/or a 19-norderivative thereof. The term activated derivative is used herein to indicate the typical enolor acetal-derivatives, such as enol ethers, enol esters, hemiacetals or acetals of the 3-keto function, and preferably the alkyl enol ethers or dialkyl acetals of said 3- ketosteroids.

BRIEF DESCRIPTION OF THE PROCESS OF THE INVENTION The process of this invention is illustrated schematically by the flow chart below wherein: Formula III represents the l7ozor 17 8-hydroXy estratriene starting material, whose hydroxy group in 3-position is preferably protected under the form of an ether or an ester; Formulae IV and V represent the 3-ketosteroids of the androstane, cholestane and pregnane series and their 18-homo and 19-nor analogs which are used in the process of this invention under the form of the corresponding activated derivatives (enol ethers or acetals), as defined above; Formulae VI and VII derivatives (enol ethers or acetals), as defined above; Formulae VI and VII represent the disteroidyl compounds resulting from the above reaction.

with organic or inorganic bases. In the case of the acid esters, the metal salts are commonly used, such as the alkali and alkaline earth metals. Esters of polybasic inorganic acids, such as sulfates, phosphates and the like, are also of particular interest since they provide watersoluble esters commonly used in steroid hormone therapy.

The hydrocarbon radical defined by the substituent R may be selected from aliphatic, cycloaliphatic, arylaliphatic and aromatic radicals containing up to 9 carbon atoms.

DETAILED DESCRIPTION OF THE INVENTION The process of this invention is usually carried out under anhydrous conditions, in a suitable solvent such as benzene, toluene, dimethylformamide or isooctane, and in the presence of a suitable acid catalyst, such as p. toluene-sulfonic aci'd, naphthalene-sulfonic acid, pyridine p. toluene-sulfonate, pyridine ehlorhydrate, and the like. The reaction is preferably accomplished at a temperature higher than C. for a period from about 30 minutes to about 4 hours.

Referring now to the Formulae VI and VII of the drawing it will be noted that they contain all the substituents shown by the Formulae I and II. In particular the rings A and B of the resulting disteroidyl compound have one of the possible structures (a)-(e), as defined above, and the C carbon atom and the substituents R, R R R R R X, Y have the above stated meanings with the exception that:

(1) R is never an alkoxyalkyl group,

( 2) R is never a free hydroxy group and in the carbon atom C'l7' A is never either hydrogen or an alkoxyalkyl group. In order to obtain compounds in which R is a free hydroxy group and in the carbon atoms C A is a hydrogen atom, the compounds of formula VI and VII can be submitted to alkaline hydrolysis.

The compounds in which R and/or A are represented by an alkoxyalkyl group are obtained by submitting the corresponding 3- and/or 17-hydroxy compounds to etherification.

The present invention includes all those compounds which can be obtained through obvious reactions, such as saponification, reduction, oxydation, condensation and acylation carried out upon keto and/or hydroxy groups which are present in the disteroidyl derivative thus obtained.

The structure of the disteroidyl derivative obtained through the etherification of a 17aor 17/3-estradiol (III) with a substituted or unsubstituted alkyl enol ether or dialkyl acetal of a keto-steroid (IV or V) strictly depends from the nature of the 3-keto-steroid itself. The following scheme is given:

Structure of the rings A and B in Enolether or acetal the disteroidyl Parent 3keto compound starting materials compound 3-keto-5a steroid B-ketofia-steroid enol- (a) A one, 5a.

ether or acetal. B-keto-Sfl steroid 3-keto-5B-steroid enol- (b) A -ene, 5,8.

A -3-keto 5d-St8l'0id (c) A -diene, 5a.

(c A -diene, 55.

A ai-keto steroid A -3-ketosteroid or alkoxy A -3-keto steroid.

The preferred alkylor substituted alkyl enol ethers, starting materials, are those containing from 1 to 7 carbon atoms, such as methyl-, ethyl-, fi-halogen substituted ethyl-, propyl-, butyl-enol ether and their isomers. Furthermore the cycloalkyl-enol ethers containing 5 or 6 carbon atoms or an allyl-enol ether are also used. As acetal, the dimethylor diethyl-acetal is preferably used.

PREPARATION OF THE STARTING MATERIALS (a) and (b). The acetals of saturated S-ketones (5a or 55) can be easily prepared by simultaneous action of an alkyl orthoformiate and of the corresponding alcohol over the 3-ketone according to Serini and Kosters method (Ber. 71, 1766; 1938). The enol ethers of satu rated 3-keto-steroids (5a or 5B) may also be obtained by reacting the 3-keto-steroid with methanol in the presence of an acid catalyst, according to the method of M. Janot et al. (Bull. Franc. 2109, 1961) or to the method of J. Slomp et al. (J.A.C.S. 77, 1216; 1955).

By submitting a dialkyl acetal of-the saturated 3-ketone to pyrolysis under conditions analogous to those disclosed by H. H. Inhoifen and C011. (Ann. 568, 52, 1950), the corresponding enol ether is obtained. It will have the structure: (a) A -ene, Set if the 3 keto-steroid belongs to the series 5a, or the structure; (b) A -ene, 55 if the 3-keto belongs to the series 58.

The enol ethers of the 3-keto-5u-steroids can be obtained, according to the method described in U.S. Pat. No. 3,118,917, by catalytic hydrogenation of the double bond in position 5 from the corresponding enol ethers of analogous A -3-ketones (that is ethers of 3-oxy-A -diene steroids), followed by spontaneous migration of the remaining double bond from the 3:4 position to the 2:3 position.

The enol ethers of 3-keto SOL-SICI'OICIS having a A -ene structure may be obtained, according to the method described in our U.S. Pat. No. 3,264,329, by catalytic hydrogenation of the corresponding enolethers of A -3-ketosteroids in the presence of a catalytic amount of a basic substance.

(c) and (c). The enol ethers of A -3-keto-5a-steroids having the A -diene, 5a structure can be obtained by submitting to pyrolysis the triethers of 1a,3,3-trihydroxy- Set-steroids, as described in British Pat. No. 1,203,278 and as disclosed and claimed in the U.S. patent application Ser. No. 202,572, filed Nov. 26, 1971, now Pat. No. 3,780,072.

The pyrolysis reaction is preferably carried out at a temperature of from 60 C. to 155 C., in the presence of a suitable acid catalyst.

The triethers of 1:1,3,3-trioxysteroids-starting materials for the above-mentioned application-are disclosed and claimed in the U.S. Pat. No. 3,475,467. They may be obtained by treating the A -3-keto-5a-steroids with an alcohol and an orthoformiate under anhydrous conditions at a temperature lower than 60 C. in the presence of an acid catalyst.

According to the process of the present invention, both 1a,3,3-trialkoxysteroids and the corresponding A -3-keto enol ethers may be used for the condensation with 17- hydroxy-estratriene; but the formers, being the precursors of the enol ethers, have the advantage of a more immediate preparation and therefore they may be preferred starting materials for the preparation of the disteroidyl derivatives having a A -diene structure.

(d) The enol ethers of A -3 ketones may be easily prepared by submitting the A -3-keto-steroid to enol etherification with an alkyl orthoformiate or an alcohol, according to the well known procedures of the art.

When as reagent material in the method of the present invention there is used an enol ether of a A -3-ketone containing an alkyl radical higher than methyl or ethyl, the method disclosed in the U.S. Pat. No. 3,019,241 may be applied. Such method consists in submitting the methylor ethyl-enol ether to trans(enol)-etherification by means of treatment with a high alcohol.

(e) The 3-enolethers of 3-keto-A -steroids may be obtained by enol-etherification of the 3-keto-A -pregnadiene with ethyl orthoformiate and an alcohol in the presence of a strong acid catalyst as described in U.S. Pat. No. 3,068,253. In place of the 3-enolethers of 3-keto- A -steroids there may be used, for the preparation of the disteroidyl compounds having a A -triene structure, the corresponding alkyl enol ethers of 1a-alkoxy-A -3-ketones (or 1u,3-dialkoxy-A -dienes). These compounds are obtained by submitting the A -3-ketosteroids to the simultaneous action of an alkyl orthoformiate and of the corresponding alcohol under anhydrous conditions at a temperature lower than 60 C, in the presence of a suitable acid catalyst.

The method for preparing 1a,3-dialkoxy-A -diene steroids of the pregnane series is disclosed in our U.S. Pat. No. 3,506,650. This method may be applied to the preparation of corresponding la,3-dialkoxy-A -diene steroids of the androstane series and of their 19-nor or 18-homo derivatives.

The compounds of the invention proved to pocess interesting pharmacological properties which differ from those produced by the two constituting steroid entities when separately administered. In general, the compounds of the invention are potent, long-acting estrogenic agents, suitable for oral and parenteral administration and this is particularly evidenced in those disteroidyl compounds in which the hydroxy group in the 17-position has the 17,8- strueture.

In particular, when the l7-hydr0Xy-estratriene is the 17,8-estradiol and its 3-esters or 3-ethers as above defined and the other etherifying entity is an enol ether of the androstane, 19-norandrostane and progestinic series, disteroidyl compounds are obtained having a high and prolonged oestrogenic, contraceptive and anti-androgen activities.

When the 17-hydroxy-estratriene is still the 17B-estradiol and the other etherifying entity belongs to the cortical series, the resulting disteroidyl ethers show both estrogenic and corticoid properties and displays a significant antiinfiammatory activity. The estratriene moiety has a potentiating or synergistic efiect on the anti-inflammatory activity of corticoids while the activity on thymus, spleen and adrenals are generally reduced in the disteroidyl (estrocorticoid) compounds.

When, on the contrary, the l7-hydroxy-estratriene is the 17u-estradiol and a 3-ester or 3-ether thereof or a 17B-estradiol optionally substituted at positions 2 or =6 or 16, and the other etherifying entity is as above described, disteroidyl ethers having attenuate estrogenic properties are obtained. In these compounds, however, the other hormonal propertyproduced by the 3-keto moiety-is generally potentiated and the resulting disteroidyl compounds show high progestinie, contraceptive or anti-inflammatory activity.

In accordance with the invention, pharmaceutical compositions having the above described activities may be prepared by incorporating one of the active ingredients represented by Formula I or II in an inert solid or liquid pharmaceutically acceptable carrier.

Such compositions in general contain the active ingredient in an amount of from about 10p. to about mg., and preferably from about p. to 5 mg. and may be in form of tablets, powders, capsules, ampules or multiple dose flacons and other pharmaceutical forms suitable for the oral or the parenteral administration.

Hereinafter are given the pharmacological data obtained by testing some representative compounds of the invention.

DETERMINATION OF THE PROLONGED UTEROTROPHIC ACTIVITY The compounds under testing in 0.2 ml. sesame oil solu tion were administered in a single dose of 0.1 nmoles to spayed rats weighing about 44-48 g. Groups of rats were sacrificed, according to the administration route, at the end of the first, second and fourth week from the treatment, respectively and the uterus weight of the treated animals and controls was determined on torsion balance. The increase of the uterus weight was considered as an index of the estrogenic activity.

The results obtained are summarized, according to the administration route, in Tables I and II: as standard compounds estradiol 3 benzoate and 3-cyclopentyl1oxy-l9- nor 17u-pregna-l,3,5(10)-trien-20-yn-17-ol were chosen to be compared with the data obtained by oral administration and ethynyl estradiol and estradiol 3-ber1zoate for the Compoud administered orally 1 week 2 weeks 1,3,5(10)-trien-3-nl benzoate 48. 0i3. 18 31. Gil. 09 17fi-(ITB-propionoxy-androsta-3',5-dion-3- yloxy)-estra-1,3;5(10)-trien-3-ol benzoate 49. 4i2. 37 31. 0:1:0. 91 175- (17-0 X019-n0r-androsta-3 ,5-dien-3- ylox y)-estra 1,3,5(10)-trien-3-ol henzoate 59. 8:1:3. 49 43. 73:2. 58 17B(17-oxo-andros tit-3,5'-dien-3-yloxy)-estra- 1,13,5(10) -trien-3-ol 56. 9:2. 13 38. Qil. 89 l7fl-(17'B-hydroxy-estra-il' ,5'-dien estra-1,3,5(10) -trien3-ol 41. 6:1:1. 74 17s -(17flhydrox y-androst estrn-l,3,5(1O)-t1ien-3-ol 52. 0:1:2. 1O 36.8i1. 15 17fl-(17oxo-estra-3,5-dien-3'-yloxy) estra- 1,3,5 (10)-trien-34)l .L 71. 7:1:5. 33 43. 6:1:2. 41 176-( 17-ox o-estra3,5-dien- 3-ylo xy) -estra.-

1,3,5( 10) trien-3-ol hemisuecinate 1 59. 2:1:3. 69

1 Aqueous suspension additioned of Na2HPO TABLE II Uterut weigh t (mg) alter Compound administered sube utaueously 4 weeks Control 15. 0:1:0. 88 Ethynyl-estradiol.... 25. lit). 99 Estradiol B-benzoate 40. 1:1:4. 03 175% 20-o xo-21-aeetoxy-pregna3,5-dien-3-yloxy)-estra- 1,3,5 10) -trien-3-0l benzoate 150. 7x14. 10 17B-( 17 fl-aeetoxy-W-a-methyl-a11dr0ste-3',5-dien$- ylo xy)-estra-1,3,5(10)-trien-3-ol benzoate 171. 9:]:12. 30 175-0 1 ,20'-diox o'17a-hydrox y-21-aceto xypregna-lfi,

5-trien-3-yloxy)-est ra-1,3,5(10)-trien-3ol benzoate 173. 15:15. 70 1713-(17aaeet0 xy-20 -oxo-6-methylpregna-3 ,5 -di 811-3- ylox y) estra-1,3,-5 (10) -trien-3ol benzoate 116. 1:1:13. 30 17fl(17flecetoxy-19-nor-17-a-pregna-3,5'-dien-20-yn- 3-ylo xy) -estra-1,3,5(10) trien-3-ol benzo ate 177. 6:|:7. 74 17fl-(9a -fluoro 1173,1701 -dihydroxy 20'-oxo-21'-acetoxy- 16B methyl pregna-3,5' -dien-8 -y1o Ky) -est.ra-1,3,5(10) trien-3-ol benzoate 136. Gil i. 17fi-(eholesta -3' ,5 -dien-3' -yl0 xy) -estra-l,3,5(l0) t1ien-3- benzoat-e 188. 05:11. 00 17fl-(17B-hydroxy Ta-mathyl androsta-3,5"dien 3- yloxy) estra-1,3,5(10) trien 3 01 168. 7:1:7. 35 17B-(17B-propionoxy-5 B-androst 3-en-3ylexy) -estra 1,3,5(10) tn'en-B-ol benzoate 213. 45:10. 17fl(17fl-propionoxy androsta-3 -5-dien-3' yloxy) -est.ra-

1,3,5(10)trien-3-ol benzoate 188. 7:1:5. 80 17B-(l7 3-aeetoxy-5a androst-2-en-3'yloxy) -estra-1,3,5

(10) -trien-3-ol benz0ate 168. 1:1:14. 60 176-(20 -oxo pregna-3 ,5 -dien-3 -y1oxy) -estra.-l,3,5(10) trien-B -ol benzoate 180. 1:1:11. 50 176-(9'a-fiuoro-11,20-dioxo-17a -hydroxy-21' acetoxylfifi-methyl pregna-G,5-dien-3'-yloxy) -estra-1,3,5(10) (mien-3 01 henzoate 143. 0:t:17. 20

Tables I and II show that the compounds according to the invention exhibit a greater estrogen activity than the standard compounds.

DETERMINATION OF THE CONTRACEPTIVE ACTIVITY The contraceptive activity was determined in mature Wistar female rats weighing about 180-205 g. The compounds under testing, in 0.2 ml. sesame oil solution, were injected subcutaneously in a single dose of 0.5 umole and the following day the treated animals were caged with fertile males. Monthly autopsies of 10 animals per group gave the data summarized in Table III where it is indicated the situation up to the 90th day from the treatment. As standard compound 3-(cyclopentyloxy)-19-nor- 17u-pregna-l,3,5( l0)-trien-20-yn-l7-ol was taken.

Table III shows that the contraceptive activity of the two compounds of the invention is much higher than that displayed by the standard 3-(cyclopentyloxy)-19-n0r-17apregna-1,3,5(10)-trien-20-yn-17-ol: particularly after two months while 9 out of 10 animals treated with the standard were pregnant, none of the remaining two groups was pregnant and after three months while all the animals treated with the standard had already delivered, only one treated with l7,8-(17',8-acetoxy-19'-nor-17'a-pregna-3',5- dien 20'-yn-3'-yloxy)-estra-1,3,5(l0).-trien-3-ol acetate was pregnant andno pregnancy in the other group occurred. 17B (17'5 enanthoxy-19'-nor-17'a-pregna-3',5'- TABLE IV dien 20'-yn-3'-yloxy)-estra-1,3,5(10)-trien-3-ol-benzoate Autopsy performed on mm further assayed on female dogs at a single dose of 2 mgs./ 32%? day from Surgery kg. 8.0. displayed an antifertility effect lasting about 15 Compound administered orally mole Uterus, mg. Ovaries, mg. 5 Control 1o1.9i12.4 l45.3;l=20.6 months. After this period a normal reproductive per 3 010mmyloxydgmpnm I formance was observed. g i 160 It 3 100 2i 9 -O l 17B-(17B-hydroxy-17a-methyl- DETERMINATION OF THE ANTIGONADO- antdrolsgaghigg-ttiieng-ylloxy)- 0 5 11 4 TROPHIC ACTIVITY es ramen -0 90.11;}: 43.7:h7.1.

175-(9 -t1uoro-11B,17adihy :iroxy oxo-21- The compounds under testing, in 0.2 sesame oil solugfigEf ggfgfii xg g tion, were administered in a single dose to spayed rats n 54 a e--. 0.5 97-9=!=12.4 76.1:1=14.1

17B-(I7-oxo-19-nor-androstaweighlng about 105-125 g., the day after surgery (para- 3,i53-d5i1i;l)-)3t-y1oxg) -si)tra t biosis). Autopsy performed a few days after gave the data 15 enzoa TABLE III Autopsy on the- Treatetd th day 60th day 90th day ra S Compound (day 0) D1 P2 NP D P2 NP D1 P2 NP 3-eyc1opentyloxy-IQ-nor17a-pregna'1,3,5(10)-trien-20-yn-17-0 10 1O 9 1 10 17a iweaeetox -io nor-nm regna3',5-dien-20-yn-3-yl0xy)- 10 1 9 estra-1,3,5 (10) 4111' en-3-ol acetate 17 9-(17B-enanthoxy-19-nor-17a-pregna-3,5-dien-20-yn-3-y1oxy)- estra-1,3,5(10)-trien-3-ol-benzoate 10 10 10 10 1 Delivered; 2 Pregnant; 3 Not pregnant. summarized in Tables IV, V and VI which were com- TABLE V pared to those obtained by administration of 3-(cyclo- Si 1 Autotsy performed on 11th pentyloxy)19-nor-17a-pregna-1,3,5(10)-trien-20-yn-17-ol. 30 5; ay mm surgery Tables IV, V and VI clearly evidentiate the higher ac- Cmnpmmd Uterus, v a e- Control- 139.4 t1v1ty of our compounds in respect to the standard 3 cyclo 3wclopentyloxy 19 n0r 17a i8 8 137 8=l=14.7 pentyloxy-19-nor-17a-pregna-1,3,5( 10) -tr1en-20-yn- 17-01. re na-1,3,5(10)-trten-20- n- -o 0.5 156.5;|=8.5 129. :19.1 17 I7-oxo-androsta-3,5'- DETERMINATION OF THE PROGESTINIC 35 gin-lt-ylloxyyestra-lfifi(I0)- rlen- -o 0.2 128.3 11. ACTIVITY 1719-117'B-hydroxy-estra3',5'- d: 7 69 (M213 7 I d1en-3-yloxy)-estra-1,3,5(10)- The tests were performed according to the Clauberg gftfi-ggk -7 1 1127 method on immature female rabbits weighing about 700- 40 z 'gw di naflox nstra 900 g. After a 6-day priming with estardiol (5 ag/0.2 ml. ig giig aig fg figfij oil/die/ subcutaneously) the compounds under examinagig o 2 n9 6H5 7 53:10 6 tion were daily administered for 5 days by oral route. B-( 'fiygrg gygam r-g re Autopsy was performed the day after the end of the treatlo1$iestra-1,?5(10) t%en- -0 0.2 ment and the data evaluated according to McPha1l (I. 98 41b 9 3 -7 Physiol. 83, 145, 1934). i i f g g 5 0 2 1' 11- *0 811208 e 3 Hydroxy 17;8-(17'5-acetoxy-1'9'-nor-17a-pregna- 17B-(17/3-aeeto1y-19-n0r-17a- 108 3 431::

r r r I 3,5' dien 20 -yn-3 -yloxy)-estra-1,3,5(1O)-tr1en-6-onef t f ?f 2 r I -o aceae.-. 0.2 1. benzoate and 17a (17 5 hydroxy 19 nor 17 a pregna 3 1 8 :11 1 81 2113.9 5 diene-ZO -yn-3'-yloxy)-estra-l,3,5(10)-tr1en-3 01 tested pm'r-y w-est a-l3,500)- d h h trlenfi l n at 0.2 127.15: 7.2 82. 8;!:9.2 at equlmolar oses in comparison wit t e parent com 7, agydien-3-yloxy)=estra.-1,3,5(10)- ound norethindrone ace a w Shown to be as P trien-3-o1benzoate 0.2 14041110 68.0;1=16.2 gestlnlc agents twice as active as the standard. 55

TABLE VI DETERMINATION OF THE CORTICOID ACTIVITY single Autolsayg gerformed on 10th om surgery The compounds under examination were generally gfifigfiigg m igfif Uterus Ovaries evaluated for their anti-inflammatory activity according Cont rol 1641:1510 6*1149 to the granuloma pouch assay (Nezamis-Acta Endocr. 25, 105) on albino rats. The dorsal skin of the animals 53%75jgijiigg lii aj"' 101-31540 54-7i1479 pregna-3,5-dien-20- n-3'- was shaved with an electric clipper and before air then yloxy) 425M413 croton 011 were in ected in the middle of the back. The s-ogg a an 0.1 37. 4:1:5. 02 32.25.61 compounds were administered directly into pouch, subegn 5 ii%i f' cutaneousl or orall The volu y y me of the exudate c l 3-01 acetate 0.1 613331.31 a2.2=i=2.97 Iected after autopsy was considered as an index of the Q993 };5Y& g'

egnaiennanti-mflammatory activity. gv ,3. 0)-tiien- -o enzoae The compounds under examination tested taking as l7fl l7'a-enangho -is -nor- 0 1 57 85216 re a- ,5 d'en-20- standard compound the mixture of the two steroids cong'q r l g w sttrad,3,g(10)-t1ien- -O enzoa stituting the disteroidyl-ether, showed an enhancement of 17fl-(l7flgcgtgty-l9 rtor-l7 22 pregna ien-20- -3- the anti inflammatory activity in respect to that displayed yloxy)'estra-l,3,5(10) iien-3- by the parent SICIOld, ol-butyme .1 44. 1:1:3. 22 31.3:1z0, 67

The following examples are given to illustrate the invention without limiting it.

EXAMPLE 1 17p-(17-oxo-19'-nor-androsta-3 ',5 '-d'ien-3'-yloxy -estra- 1,3,5-( 10) -trien-3-ol benzoate 5 g. l9-norandrost-4-en-3,17-dione 3-ethyl enol ether were added toa boiling solution containing 6.5 g. estradiol 3-benzoate and 50 mg. p. toluenesulfonic acid in 800 ml. toluene and the mixture was heated wit-h rapid solvent distillation for about 60 minutes. After addition of some drops of pyridine and complete removal of the solvent under reduced pressure, the residue was taken up with methanol, filtered and recrystallised from methylene chloride: ethanol to give 8 g. 17B-(17-oxo-19-norandrosta-3,5'-dien- 3-yloxy)-estra-1,3,5(l0)-trien 3 ol benzoate, melting at 272-278 C. By further recrystallisation a melting point of 283-286 C. and [oz] =33 C. (dioxan, 0.: l were obtained.

EXAMPLE 2 17 S-(17'B-propionoxy-androsta-3'5-dien-3-yloxy)- estra-l,3,5(10)- trien-3-ol benzoate A mixture of 1.5 g. testosterone 3-ethyl enol ether 17- propionate and 1.5 g. estradiol 3-benzoate in 20 ml. dimethylformamide was treated with g. p. toluenesulfonic acid, then heated on an oil bath at 120-150" C. for 40 minutes and successively at 180-200 C. for minutes. After addition of some drops of pyridine and removal of the solvent under reduced pressure, the residue was taken up with methanol, filtered and recrystallised from methylene chloride: methanol to give 2 g. l7fl-( l7' 3-propionoxyandrosta-3',5=dien-3-yloxy)-estra-1,3,5(10)-trien 3 o1 benzoate, melting at 22l224 C. [a] =58 C. (dioxan, c.=1%

EXAMPLE 3 17,9-( l7'fi-acetoxy-5'a-androsta-1,3-dien-3'-yloxy)- estr'a-l ,3,5 10) -trien-3-ol benzoate Grams 2 1a,3a3B-trimethoxy-5a-androstan-1713-01 acetate were added to an anhydrous boiling solution of 2 g. estradiol 3-benzoate and '60 mg. pyridine p. toluenesulfonate in 1000 ml. benzene. The mixture was heated with solvent distillation for 150 minutes. After addition of some drops of pyridine and complete removal of the solvent under-reduced pressure, the residue was taken up with methanol, filtered and recrystallised from methylene chloridezmethanol to give 1. 6 g. 17fl(17}8-acetoxy-5aandrosta-l,3'-dien-3'-yloxy)-estra 1,3,5(10) trien-3-ol benzoate melting at 270-275 C., [a] =+41.5 (dioxan, c.=1%).

' EXAMPLE 4 3'-heptyloxy.- 17 ,8-( 17'B-propionoxy-5'a-androst-2'-en- 3'-yloxy)-estra-1,3,5( 10) -triene A mixture of 2.7 g. 5a-dihydrotestosterone 17-propionate 3,3-dimethyl acetal and 2.7 g. estradiol 3-n-heptyl ether in, 15 ml. dimethylformamide was treated with 15 mg. p. toluene sulfonic acid by operating as above described in Example 2, to give 3.2 g. 3-heptyloxy-l7fi- (17'fi -'propionoxy 5'0: androst-2en-3'yloxy)-estra- 14 1,3,5(10)-triene melting at 152-156 C., [a] =|49.5 C. (dioxan, c.=0.5%).

EXAMPLE 5 17,6-(17' 3-enanthoxy-19'-nor-17'a-pregna-3',5-dien- 20'-yn-3'-yloxy)-estra-1,3,5 10)-trien-3-ol acetate A solution of 3 g. 17a-ethynyl-19-nortestosterone l7-enanthate in 3 ml. anhydrous tetrahydrofurane and 2.4 ml. ethanol was treated with 3 ml. triethylortheformiate and 30 mg. p. toluenesulfonic acid and kept at room temperature for 45 minutes under occasional stirring. After addition of 0.03 ml. pyridine the excess of triethylorthoformiate was removed by evaporation under reduced pressure and the oily residue was dissolved in 20 ml. benzene and added to a boiling solution of 3.8 g. estradiol 3-acetate and pyridine p. toluenesulfonate in 5.000 ml. benzene. The reaction mixture was heated with rapid solvent distillation for about 30 minutes, then 0.4 ml. pyridine were added. After complete removal of the solvent under reduced pressure, the residue was taken up with ethanol and filtered, to give 3.7 g. 17/3-(175- enanthoxy 19' nor 17'a-pregna-3',5-dien-20'-yn-3'- yloxy)-estra-1,3,5(10)-trien-3-ol acetate, melting at 126" C. The product, dissolved in benzene, filtered through alumina and successively recrystallised from ether-methanol showed a melting point of -143 C. (with softening 120 C.), [u] =-92.5 C. (dioxan, c.=1%).

5'a-androst-2-en-3-yloxy)-estra-1,3,5(10)-trien- 3-01 cyclopentylpropionate.

TABLE VIICont1uued EXAMPLE 125 17;3-( 17'13-hydroxy-19-nor-17'a-pregna-3',5- dien-20-yn-3'-yloxy) -estra-1,3,5 10) 301 A suspension of 11.9 g. 17fi-(17p-acetoxy-l9'-nor- 17a pregna-3,5'-dien-20'-yn- -yloxy)-estra-1,3,5(10)- trien-3-ol benzoate (Ex. 39) in 250 ml. methanol was treated with a 5% methanolic potassium hydroxide solution and refluxed for 7 hours. After evaporation under reduced pressure the residue was diluted with water, and 160 ml. 10% hydrochloric acid were added, and the mixture was bubbled through carbon dioxide for about 30 minutes. The precipitate was filtered, washed with water and crystallized from methanol to give 8.95 g. 1713-(17'6- hydroxy 19'-nor-17a-pregna-3',5'-dien-20'-yn-3-yloxy)- estra-1,3,5(10)-trien-3-ol, melting at 260-263 C. [a] 119 C. (dioxan, c.=1%).

According to the above procedure the following disteroidyl ethers are obtained.

TABLE VIII Ex. No. Disteroldyl ether Prepared from- End compound Ex. 7.

End compound Ex. 16.

End compound Ex. 52.

End compound Ex. 55.

End compound Ex. 56.

End compouud Ex. 66.

an X.

End compound Ex. 13

and Ex. 14. End compound Ex. 93.

End compound Ex. 2.

End compound Ex. 17,

Ex. 18 and Ex. 19. End Compound Ex. 48.

End compound Ex. 98

and Ex. 100.

End compound Ex. 53.

End compound Ex. 57.

End compound Ex. 62.

End compound Ex. 103;

End compound Ex. 102.

End compound Ex. 1

18 EXAMPLE 148 17,8- (20-oxo-21'-hydroxypregna-3',5-dien-3'-yloxy)-estra-1,3,5( 10 -trien-3 -ol benzoate A solution of 1.80 g. of 17 3 -(20'-oxo-21-acetoxypregna-3',-5-dien-3'-yloxy)-estra 1,3,5(10)-trien-3-ol benzoate (Ex. 52) in ml. of tetrahydrofurane and 90 ml. of methanol kept under nitrogen, was treated with 1.80 ml. of 1M methanol solution of sodium methoxide. After stirring at room temperature for 20 minutes, the solvent was evaporated under reduced pressure and the residue taken up with water and filtered. A crystallization from methylene chloride-methanol gave 1.20 g. of crystals of 17e-(20'-0xo-21'-hydroxypregna 3',5' dien-3'-yloxy)- estra-1,3,5(10)-trien-3-o1 benzoate, melting at 175-177" C. (dec.).

According to the above procedure the following disteroidyl ethers are obtained.

TABLE IX Ex; No; Dlsteroidyl other End compound Ex. 56.

End compound Ex: 57.

End compound Ex. 61.

End compound Ex. 62.

End compound Ex. 101.

EXAMPLE A suspension of 2 g. 17/8-(17B-acetoxy-19'-n0r-17'apregna 3',5'-dien-20'-yn-3'-yloxy)-estra-1,3,5(10)-trien- 3-01 acetate (Ex. 36) in 20 ml. tetrahydrofurane and 80 ml. methanol was treated with 10 ml. of a 10% potassium carbonate aqueous solution and kept under stirring at room temperature for about 4 hours.

The reaction mixture was then poured into 300 ml. water, and the precipitate filtered and recrystallized from methylene chloridezmethanol to give 1.5 g. of 17,9-(17'5- acetoxy 19'-nor-1Tot-pregna-3',5-dien20'-yn-3'-yloxy)- estra-1,3,5(10)-trien-3-ol melting at 281284 C. (with softening at 270 C., [oz] =111 C. (dioxan, c.=1%.).

According to the above procedure the following disteroidyl ethers are obtained.

TABLE X Prepared trom- "End compound Ex. 106.

End compound Ex. 123.

End compound Ex. 111.

End compound Ex. 124.

EXAMPLE 17,6- 17-0xoestra-3',5 -dien-3 '-yloxy) -estra- 1,3,5 10) -trien-3-ol hemisuccinate A solution of 1.4 g. of 17;3-(17'-oxoestra-3,5-dien-3'- yloxy)-estra-1,3,5(10)-trien-3-ol (Ex. 139) and 4.2 g. of succinil anhydride in 50 ml. of pyridine was kept overnight at room temperature. The mixture was then poured into 480 ml. of saturated salt solution and extracted with ether. The organic layer was separated, dried on anhydrous sodium sulfate and the solventremoved under reduced pressure. The residue was crystallized from methylene chloride-methanol to give 800 mg. of crystals of 17fi-(17-oxoestra-3',5'-dien-3'-yloxy) estra 1,3,5 (10)- trien-S-ol hemisuccinate, melting at 170-l73 C.

TABLE XI Ex. No. Dlsteroidyl other N'rE.--Analogously by reaction with the anhydride of the acetic, proplonie, butyrie, Valerie, enanthic, caproic, benzoic, malomc, phthahc flfigaiglldtfiflfic acid the corresponding esteiified disteroidyl ethers were 0 n Prepared from- End compound Ex. 155.

End compound Ex. 159.

End compound Ex. 141.

End compound Ex. 149.

End compound Ex.

End compound Ex. 146.

End compound Ex. 133.

End compound Ex. 137.

End compound Ex. 125.

EXAMPLE 172 17p- 17fl-( 1"-ethoxyetho-xy) 19'-nor- 17 a-pregna-3',5 dien-20'-yn- -yloxy )-estra- 1,3,5 -trien-3 -ol acetate A solution of 1 g. 175-(17'fl-hydroxy-19'-nor-17":- pregna-3,5'-dien-20'-yn 3' yloxy)estra-l,3,5 (10)-trien- 3ol acetate (BX. 170) in 10 ml. anhydrous tetrahydrofurane was treated with 10 mg. pyridine tosylate and 2 ml. ethyl vinyl ether and kept at room temperature for hours. The solvent wasevaporated and the residue was crystallized from ethanol, to give 750 mg. 17,8-(l7'fl-(1"- ethoxyethoxy)-19'-nor-17'a-pregna-3',5'-dien yn-3'- yloxy)-estra-1,3,5(10)-trien 3 o1 acetate, melting at 126-131 C., [c];,=9-8 C. (dioxan, c. =1%).

According to the above procedure 3-( l'-ethoxyethoxy)- 17fl-(17 fi-(l"-ethoxyethoxy)-19"-nor 17"a pregna- 3",5"-dien-20"-yn-3"-yloxy)estra-1,3,5(10) triene starting from the end-compound of Ex. 125 and 17 B-(17;8-( 1"- ethoxyethoxy)-19'-nor-17a-pregna 3',5' dien-20"-yn-3'- yloxy)-estra-1,3,5(10)-trien-3-ol enanthate starting from the end-compound of Ex. 171 were obtained.

20 EXAMPLE 173 175 1 1',20'-d10X0-17'0z,2 1-dihydroxypregna-3 ',5'-dien- 3'-yloxy -estra-l,3,5( 10) -trien-3-ol benzoate 21'-sulphate sodium salt In a flask provided with a stopper, 9.4 ml. anhydroxy pyridine and 0.42 ml. acetic anhydride were added to 0.721 g. anhydrous sulphate pyridine and the mixture was stirred for 30 minutes. A solution of 1 g. of 17p-(11',20'- dioxo-l7a,21'-dihydroXypregna-3,5'-dien 3 yloxy)- estra-l,3,5(10)-trien-3-ol benzoate (BX. 149) in 10 ml. pyridine was added and the mixture kept under stirring overnight at room temperature. The content of the flask were evaporated under reduced pressure at 40 C. and the residue was taken up with Water, adjusted to a pH 11-12 with a 5% aqueous solution of sodium hydrate and extracted with successive portions of n-butanol. Then butanol was removed by a short leating and the residue, taken up with ether, gives 1 g. 175-(1l,20-dioxo-17'a,21-dihydroxypregna 3,5' dien-3-yloxy)-estra-l,3,5(10)-trien- 3-01 benzoate 21'-sulphate sodium salt.

Analogously to the above procedure starting from the 3-hydroxy free or 17'B-hydroxy free or 2l'-hydroxy free disteroidyl ethers of any preceding example, the corresponding 3- or 17'13- or 21'-sulphate alkaline salt was obtained respectively.

EXAMPLE 174 To a solution of 0.1 ml. of redistilled phosphorus oxychloride in 5 ml. of pyridine is added at 25 C. with stirring a solution of 400 mg. of 17B(9'afi1101O-11',20'- dioxo-17'a,2l-dihydroxy-16fi-methylpregna 3',5' dien- 3'-yloxy)-estra-1,3,5(10)-trien-3-ol S-benzoate (Ex. 150) in 5 ml. of anhydrous pyridine. To the dichloride thus formed 20 ml. of water is added at the rate that the reaction temperature does not exceed 10 C. The mixture is then allowed to remain at room temperature for 10 minutes and the pyridine is removed in vacuo without applying external heat. The resulting residue is taken up in water, then sodium bicarbonate solution is carefully added until the mixture reaches pH 7. After extraction with chloroform, the aqueous phase is concentrated under vacuum to dryness. The residue is dissolved in methanol and the l7p-(9'a-dluoro 11',20 dioxo-l7'a,21'-dihydroxy- 16'fl-methylpregna-3,5-dien 3' yloxy) -estra-1,3,5 (10)- trien-B-ol 3-benzoate 21'-disodium phosphate precipitated by addition of 1:1 mixture of anhydrous ether and absolute ethanol.

Analogously to the above procedure starting from the 3-hydr0xy free or 17'B-hydroxy free 21-hydroxy free disteroidyl ethers of any preceding example, the corresponding 3- or 17'6- or Elf-phosphate alkaline salt was obtained respectively.

We claim:

1. Disteroidyl-ethers of formula:

21 wherein the wavy lines indicate that the oxygen atom linked in 17-position to the estratriene nucleus and the optional substituent in position-16 of the second steroid nucleus may assume the a or p configuration;

R represents hydrogen, an acyl radical containing up to 12 carbon atoms, a hemisuccinyl, hemimalonyl, hemiglutaryl, hemiphthalyl radical, a sulfate or phosphate radical or a hydrocarbon radical selected from the group consisting of an aliphatic radical containing up to 8 carbon atoms, and a cycloaliphatic radical containing 5 or 6 carbon atoms;

R represents hydrogen or methyl;

R represents hydrogen, halogen, methyl, or an alkanoyloxy radical containing up to 3 carbon atoms;

R represents methylor ethyl;

Yrepresents hydrogen or fiuoro;

X represents hydrogen, fi-hydroxy or ketonic oxygen; the

carbon atom at'the' 1.7 position having one of the following structures:

R! R1 R1 R1 2' 2' '2' H H \\/H wherein, when either (a), (b) or (c) is present, position 1', or 2 may contain a hydrogen or a methyl group. 2. Disteroidyl-ethers of formula:

wherein the wavy lines indicate that the oxygen atom linked in 17-position to the estratriene nucleus and the optional substituent in position 16 of the second steroid nucleus may assume the a or B configuration;

R represents hydrogen, an acyl radical containing up to 12 carbon atoms, a hemisuccinyl, hemimalonyl, hemiglutaryl, hemiphthalyl radical, a sulfate or phosphate radical or a hydrocarbon radical selected from the group consisting of a cycloaliphatic radical containing 5 carbon atoms;

R represents hydrogen or methyl;

R, and R represent each hydrogen, hydroxy or an acyloxy group containing up to 4 carbon atoms;

R, represents an OAcyl group in which Acyl is selected from the group consisting of an acyl radical containing up to 12 carbon atoms, a hemisuccinyl, hemimalonyl, hemiglutaryl, hemiphthalyl radical, a sulfate and a phosphate radical, when R is hydrogen or hydroxy; R represents an acyloxy group containing up to i 7 carbonatoms, inclusive, when R, is hydrogen or hydroxy;

R represents hydrogen, methyl, or methylene;

R and R may form together a cyclopentylidenedioxy radical;

R and K, may form together an isopropylidenedioxy radical or a 1'-methylbenzylidenedioxy radical;

Y represents hydrogen, fluoro or chloro;

X represents hydrogen, p-hydroxy, ketonic oxygen or chloro when also Y represents chloro; and the rings A and B having one of the following structures:

wherein position 6"may be substituted by a halogen atom, or by a methyl group where structure (a) is present. 3. Disteroidyl-ethers of formula:

--CEOH wherein R represents hydrogen, an acyl radical containing up to 12 carbon atoms, a hemisuccinyl, hemimalonyl, hemiglutaryl, hemiphthalyl radical, a sulfate or phosphate radical or a hydrocarbon radical selected from the group consisting of an aliphatic radical containing up to 2 carbon atoms, and a cycloaliphatic radical containing 5 carbon atoms;

R represents methyl or ethyl; and

A represents hydrogen, an acyl containing up to 12 carbon atoms, a hemisuccinyl, hemimalonyl, hemiglutaryl, hemiphthalyl radical or a sulfate or phosphate radical. 4. (9'0: Fluoro 11'fi,17'a dihydroxy 20 oxo 21 acetoxy l6a methylpregna 1',3,5' trien- 3 yloxy) estra 1,3,5(10 trien 3 ol benzoate.

5. 17a (19 Nor 20' oxopregna 3',5' dien 3'- yloxy) estra 1,3,5(10) trien 3 ol benzoate.

6. 17a (17'0: Acetoxy 19' nor 20' oxopregna- 3',5' dien 3 yloxy) estra 1,3,5(10) trien 3 ol propionate.

7. 175 (17' 0x0 19' norandrosta 3',5' dien 3'- yloxy) estra 1,3,5(10) trien 3 o1 benzoate.

8. 17B (17'fi =Hydroxy 19' nor 17'a pregna- 3,5' dien 20 yn 3' yloxy) estra 1,3,5(10) trien- 3-01.

9. 17B (17'B Acetoxy 19 nor 17'a pregna- 3',5' dien 20' yn 3 yloxy) estra l,3,5(10) trien- 3-ol benzoate.

10. 17B (175 Enanthoxy 19 nor 17' pregna- 3',5' dien 20' yn 3' yloxy) estra l,3,5(10)- trien-3-ol benzoate. 

